Immunological functions of CD4^+ regulatory T cells induced by 4C8-costimulation

4C8共刺激诱导的CD4^调节性T细胞的免疫功能

• 批准号: 14570425
• 负责人: MASUYAMA Jun-ichi
• 金额: $ 1.79万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570425/
• 关键词: anti-4C8Ab; costimulation; regulatoy T cell; cytolcine; 4C8; 樹状細胞

CD4^+CD25^+ regulatory T (Treg) cells naturally occur in mice and humans, and similar Treg cells can be induced in vivo and in vitro. However, the molecular mechanisms that mediate the generation of these Treg cell populations remain unknown. We previously described anti-4C8 monoclonal antibodies that inhibit the post-adhesive transendothelial migration of T cells through human endothelial cell monolayers. We demonstrate here that Treg cells are induced by costimulation of CD4^+ T cells with anti-CD3 plus anti-4C8. The costimulation induced full activation of CD4^+ T cells with high levels of IL-2 production and cellular expansion that were comparable to those obtained on costimulation by CD28. However, upon restimulation, 4C8-costimulated cells (4C8 Treg cells) produced high levels of IL-10 but no IL-2 or IL-4, and maintained high expression levels of CD25 and intracellular CDI 52, as compared to CD28-costimulated cells. The former cells showed hyporesponsiveness to anti-CD3 stimulation and suppressed the activation of bystander T cells depending on cell contact but not IL-10 or TGF-β The suppressor cells developed from CD4^+CD25^+CD45RO^+ cells. IL-7 and IL-15 promoted proliferation of 4C8 Treg cells. 4C8 Treg cells inhibited activation of CD4^+T cells in response to coculture with dendritic cells developed from peripheral blood monocytes. The results suggest that 4C8 costimulation induces the generation of Treg cells that share phenotypic and functional features with CD4^+CD25^+ T cells, and that CD25 memory T cells may differentiate into certain Treg cell subsets in the periphery. Furthermore, 4C8 Treg cells may have potential to suppress allo-rejective response due to organ transplantation.

CD 4 ^+ CD 25 ^+调节性T（Treg）细胞天然存在于小鼠和人类中，并且可以在体内和体外诱导类似的Treg细胞。然而，介导这些Treg细胞群产生的分子机制仍然未知。我们先前描述了抗4C 8单克隆抗体，其抑制T细胞通过人内皮细胞单层的粘附后跨内皮迁移。我们在此证明，Treg细胞是通过抗CD 3抗体和抗4C 8抗体共同刺激CD 4 ^+ T细胞而诱导的。共刺激诱导了CD 4 ^+ T细胞的完全激活，产生了高水平的IL-2，细胞扩增与CD 28共刺激获得的结果相当。然而，在再刺激时，与CD 28共刺激的细胞相比，4C 8共刺激的细胞（4C 8 Treg细胞）产生高水平的IL-10但不产生IL-2或IL-4，并且维持高水平的CD 25和细胞内CD 152表达。前一种细胞对抗CD 3刺激表现出低反应性，并抑制旁观者T细胞的活化，这依赖于细胞接触，而不是IL-10或TGF-β。抑制细胞由CD 4 ^+ CD 25 ^+ CD 45 RO ^+细胞发育而来。IL-7和IL-15促进4C 8 Treg细胞增殖。4C 8 Treg细胞可抑制与外周血单核细胞分化的树突状细胞共培养后的CD 4 ^+T细胞活化。结果表明，4C 8共刺激诱导Treg细胞的产生，这些Treg细胞与CD 4 ^+ CD 25 ^+ T细胞具有相同的表型和功能特征，并且CD 25记忆T细胞可以在外周分化为某些Treg细胞亚群。此外，4C 8 Treg细胞可能具有抑制由于器官移植引起的同种异体排斥反应的潜力。

项目成果

Masuyama, J.et al.: "A novel costimulation pathway via the 4C8 antigen for the induction of CD4^+ regulatory T cells."Journal of Immunology. 169. 3710-3716 (2002)

Masuyama, J.等人：“通过 4C8 抗原诱导 CD4^ 调节性 T 细胞的新型共刺激途径。”免疫学杂志。

Masuyama, J.: "A Novel Costimulation Pathway via the 4C8 Antigen for the Induction of CD4^+ Regulatory T cells"J.Immunol.. 169. 3710-3716 (2002)

Masuyama, J.：“通过 4C8 抗原诱导 CD4^ 调节性 T 细胞的新型共刺激途径”J.Immunol.. 169. 3710-3716 (2002)

Masuyama, J, et al.: "A novel costimulation pathway via the 4c8 antigen for the induction of CD4^+ regulatory T cells."Journal of Immunology. 169. 3710-3716 (2002)

Masuyama, J 等人：“通过 4c8 抗原诱导 CD4+ 调节性 T 细胞的新型共刺激途径。”免疫学杂志。

Masuyama, J.: "A novel costimulation pathway via the 4C8 antigen for the induction of CD4+ regulatory T cells"J.Immunol.. 169. 3710-3716 (2002)

Masuyama, J.：“通过 4C8 抗原诱导 CD4 调节性 T 细胞的新型共刺激途径”J.Immunol.. 169. 3710-3716 (2002)